Binding of postsynaptic histamine onto its H3R limits fluxes of not only histamine but also a variety of other important neurotransmitters, e.g., acetylcholine, dopamine, glutamate, noradrenaline, serotonin, GABA, etc. (e.g., T. A. Esbenshade, et. al., Mol. Intervention, v. 6, pp. 77-88 2006). In contrast, H3R antagonists (also known as inverse agonists) could increase these neural transmitting fluxes for treating diverse groups of CNS disorders (e.g. cognitive, psychiatric, neuro-motor, pain, etc). (http://molpharm.aspetjournals.org/content/molpharm/90/5/649.full.pdf, accessed Feb. 26, 2017; a review of recent patent application on H3R antagonist, D. Lazewska et. al., Expert Opin. Therapeutic Patents, v. 28, pp. 175-196 2018 and references cited therein).
Ongoing clinical trials of H3R antagonists to treat narcolepsy over the past decade (e.g. review-https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344488/pdf/nss-9-039.pdf accessed Feb. 26, 2018) led to EU sales approval of the 1st H3R antagonist-pitolisant (brand name=Wakix; http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002616/human_med_0 01955.jsp&mid=WC0b01ac058001d124, accessed Feb. 26, 2018). While Wakix and sodium oxybate (brand name-Xyrem; its EU sales approval: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000593/human_med_001163.jsp&mid=WC0b01ac058001d124, accessed Feb. 26, 2018) are the current drugs sold to specifically treat narcolepsy and cataplexy (afflicts ˜70% of the narcoleptic patients), significant fractions (˜20-40%) of initially titrated patients discontinue further drug dosing due to poor efficacy and/or toxicity (respectively https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414617/pdf/nss-9-127.pdf and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727622/pdf/main.pdfboth accessed on Feb. 26, 2018). Thus, and like patients affected by some other CNS disorders, narcoleptic patients urgently need for better drugs in order to significantly lower these fractions.
The compounds and pharmaceutical formulations disclosed in the present application are believed to exert their therapeutic benefits by, among other things, acting to antagonize H3R.